Many breast tumors and cancers of the uterus and cervix contain estrogen receptors. These receptors provide a means by which cytotoxic estrogen derivatives might be concentrated within the receptor-containing tumor cells and thus exert a cytotoxic effect that would be selective towards the tumor. Such cytotoxic estrogens should have a greater therapeutic index than the chemotherapeutic agents currently used in treatment of these cancers. Cytotoxic estrogens will be synthesized by linking cytotoxic moieties known to have high reactivity towards DNA (aziridines, mono- and bis (chloroethyl) amines, and chloroethyl nitrosocarbamates and ureas) to non-steroidal estrogens (hexestrols) or antiestrogens. High receptor binding affinity will be maintained by attaching these groups onto the side chains of hexestrol or by incorporating them in a manner that utilizes the amino group on the antiestrogen. In vitro receptor binding and covalent attachment assays will be used to determine receptor binding affinity and to classify the cytotoxic estrogens as "receptorolytic" (reacting covalently with receptor) or "receptor carried" (bound reversibly by receptor and potentially deliverable to the nucleus). The effect of these agents on uteri in organ culture and on estrogen responsive (MCF-7) and non-responsive (MDA-MB-231) human breast cancer cells will be used to determine whether their cytotoxic activity is receptormediated. Studies in animal mammary tumor systems (dimethylbenzanthracene- and nitrosomethylurea-induced and R3230AC mammary carcinomas) will be used to determine their effectiveness in vivo. These studies should result in the development of highly selective antitumor agents of potential clinical utility.